Individuals that suffer from HIV infection have a high propensity of complications in the lung. Often non-specific inflammation occurs and there is a very high frequency of infection by a variety of pathogenic microorganisms. Unfortunately these latter pulmonary complications often lead to rapid death. The mechanism by which HIV infection leads to such drastic alterations in the immunity of the lung is unknown. In this application we will test the overall hypothesis that the HIV NEF antigen, presented in HIV-infected alveolar macrophages is responsible for altered immunity in the lung. We present preliminary data derived from a new transgenic model where the HIV NEF antigen has been targeted to the macrophage compartment in transgenic mice. These transgenic mice succumb to progressive inflammation of the lung, similar to that seen in human AIDS patients. In this application several hypothesis have proposed to explain our preliminary results. These hypothesis will be tested in the specific aims of this application. We will test the hypothesis that NEF induces dysregulation of specific alveolar macrophage cytokine responses, leading to altered cytokine profiles and poor immunity to pathogens in the lung. We will also determine whether NEF expressing macrophages have altered trafficking potential in vivo, and lastly, whether clearance of pathogens by the NEF expressing alveolar macrophages in inhibited in vivo. The results from these studies should clarify the role of the HIV NEF gene in immunity within the lung following HIV infection.